Multi-modal characterization of vasculature and nanoparticle accumulation in five tumor xenograft models

Abstract

Preclinical research has demonstrated that nanoparticles and macromolecules can accumulate in solid tumors due to the enhanced permeability and retention effect. However, drug loaded nanoparticles often fail to show increased efficacy in clinical trials. A better understanding of how tumor heterogeneity affects nanoparticle accumulation could help elucidate this discrepancy and help in patient selection for nanomedicine therapy. Here we studied five human tumor models with varying morphology and evaluated the accumulation of 100 nm polystyrene nanoparticles. Each tumor model was characterized in vivo using micro-computed tomography, contrast-enhanced ultrasound and diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging. Ex vivo, the tumors were sectioned for both fluorescence microscopy and histology. Nanoparticle uptake and distribution in the tumors were generally heterogeneous. Density of functional blood vessels measured by fluorescence microscopy correlated significantly (p = 0.0056) with nanoparticle accumulation and interestingly, inflow of microbubbles measured with ultrasound also showed a moderate but significant (p = 0.041) correlation with nanoparticle accumulation indicating that both amount of vessels and vessel morphology and perfusion predict nanoparticle accumulation. This indicates that blood vessel characterization using contrast-enhanced ultrasound imaging or other methods could be valuable for patient stratification for treatment with nanomedicines.

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

“…Despite sufficient vascularization in the periphery, UPSN‐FITC uptake was severely retarded in MDA‐MB 231, when compared to 4T1 (almost five times lower; Figure A). This is in sharp contrast to previously reported observations involving larger (100–200 nm) or ultrasmall small (<6 nm) NPs, where MVD was demonstrated to play a central role in tumor uptake of NPs . These observations indicated that superficial parameters were insufficient to explain the intra‐tumoral kinetics of UPSNs, necessitating a closer look at the differences in tissue architectures of the two models.…”

“…However, blood vessels in the xenografts demonstrated significantly attenuated microstructure, with smaller diameters, mean areas, and perimeter measurements, when compared to faster growing syngeneic 4T1 tumors (Figure D–F). Interior of MDA‐MB 231 tumors demonstrated largely avascular, necrotic areas, with chaotic cellular islands, in accordance with the clinical observations in patients with aggressive tumors …”

Smart cancer nanomedicine

“…As an alternative to companion nanodiagnostics and nanotheranostics, clinically established (but intuitively significantly less specific) 'standard' imaging protocols could be considered to predict the accumulation and efficacy of passively targeted cancer nanomedicines, such as dynamic contrast-enhanced MRI 39 , CT 40 and ultrasound 41 . Furthermore, future analyses should set out to evaluate if histopathological assessment of tumour biopsies can help to stratify responders from non-responders.…”

Imaging techniques in nanomedical research

“…The interesting study by Sulheim and colleagues is another example of multimodal imaging: 33 the authors investigated the organization and density of functional blood vessels that newly developed in a tumour tissue by intense angiogenesis. Actually, angiogenesis is crucial to understand how tumour heterogeneity affects the uptake and accumulation of therapeutic agents (among which NPs in nanomedical therapy).…”